Nontoxic, biocompatible, resorbable materials that are flowable or malleable, and have grease-like or wax-like properties are highly desirable for a wide range of medical and surgical applications. Such applications include use as a lubricant to facilitate the insertion or positioning of devices such as catheters or other implantable devices, use as an adhesive putty to keep devices and materials in position during a procedure, use as a barrier to prevent the movement of fluids away from or into tissues, or to prevent adjacent tissue surfaces from sticking together, and use as an adhesive and cohesive carrier or matrix for bioactive or inert particles and drugs that can be applied directly to bone or other tissues during surgery to promote healing.
Resorbable materials used in medicine, dentistry, and surgery are often based on hydrogels, consisting of a network of hydrophilic polymers in an aqueous medium. Hydrogels are generally well suited for use in contact with body tissues, having good biocompatibility, low toxicity, and solubility or resorbability, but the physical and mechanical properties of hydrogels are dissimilar to those of hydrocarbon-based materials and are generally less than ideal for applications that require any manipulation during their use. Chemically crosslinked hydrogels may be somewhat elastic but are not malleable or flowable because their gel structure cannot be remodeled. Once the gel structure is broken, the chemical bonds that link the polymer molecules into a network cannot be restored, and thus exposure to a force beyond the elastic limit results in fracture rather than plastic deformation. Once fully cured, such hydrogels cannot be molded or manipulated, and can be difficult to keep in place.
In some other types of hydrogel, the polymer molecules are not joined by covalent bonds, but by hydrophobic or electrostatic interactions, which can be dispersed by a change in temperature, pH, or ion concentrations, or by physical manipulation. Since the bonding is reversible, such gels may exhibit true malleable or flowable properties but, because the bonding forces are relatively weak, materials of this type are usually very soft gels with a low elastic modulus and minimal resiliency.
The high water content of hydrogels is not always desirable. Hydrogels that are not fully saturated with water prior to use, or which become more osmotically active during the resorption process, will take up additional water and consequently increase in volume after implantation. It the swelling of the implanted material occurs in an enclosed space within the body there can be a significant rise in pressure with resultant tissue damage. Also, if these compounds are intended to serve as a carrier for particles, drugs or other materials to enhance local healing, the swelling is likely to cause displacement of the particles away from the intended site. A further disadvantage of such materials is that many drugs and most bioactive compounds have reduced stability in the presence of water, thus a hydrogel-based carrier for such agents would need to be supplied in dry form and not as a ready-to-use material.
Oils and waxes from petroleum, or of plant or animal origin, often have ideal mechanical and physical properties for use as putty-like adhesives, cohesive matrices, lubricants of all weights, and barriers. Examples include mineral hydrocarbons such as petroleum jelly and paraffin wax, natural hard waxes such as beeswax and carnauba wax which are esters of long chain alkanes, and many types of synthetic or modified waxes. Depending upon the average molecular weight, extent of branching and degree of unsaturation of the hydrocarbon components of these materials, their physical properties can range from liquid, through soft flowable gel, gum, malleable soft wax, brittle hard wax, to soft plastics (e.g., polyethylene). Unfortunately, these substances are hydrophobic, insoluble in water or other aqueous media, and chemically inert. As a consequence, they cannot be dissolved, resorbed, metabolized or otherwise removed by the body, and once introduced into the tissues, will remain at the site of application indefinitely. Over time, the wax or grease will cause inflammation and interfere with healing.
Although the inability of the body to resorb such materials is known, it nevertheless remains common surgical practice to use a beeswax formulation to stop bleeding from the surface of cut bone. Bone is a structure with a rich blood supply that circulates through a system of canals within the hard mineralized matrix, and extensive network of vessels within the bone marrow. Bleeding from out or damaged bone cannot be stopped by the same techniques used for soft tissues, such as by applying hemostatic clamps or electrocautery. A beeswax formulation applied to the cut surface arrests the bleeding very effectively by adhering to the bone and physically occluding the open blood vessels. The disadvantage of beeswax is that it is not resorbed, and remains at the application site long after the surgery, where causes inflammation and sometimes granuloma formation, and interferes with bone healing. As a foreign body, the residual wax may also become a focus for persistent bacterial infection. Several resorbable formulations have been developed as alternatives to beeswax-based bone wax, and for many other surgical applications, including lubricants, barriers, and matrices, but all such material in the prior art have proven to be suboptimal in terms of biocompatibility, physical properties and handling characteristics, appearance, having ingredients of biological origin, complexity of formulation, ease of manufacture, and/or stability.
Therefore, it is an object of this invention to provide an alternative to wax- and grease-based materials for use in medical, dental, and surgical applications that overcomes the known deficiencies of existing materials.
Porous implant materials are useful for the repair or reconstruction of the bony skeleton. Implants can be used to fill bony defects, or they can be to augment or replace bone or cartilage in humans or in animals. Such implants may be made by sintering small particles or beads of a fusible material such as polyethylene or metal. An alternative way to make a porous material is to blend air bubbles or leachable particles into a molten substrate, such as titanium, which is then cooled. The particles are removed by chemical means after the substrate has cooled, leaving a “negative” structure, wherein the metal fills the spaces that existed between the particles. Typically the objective is a highly porous material in which the pores form an interconnecting network. Tissue ingrowth occurs in implants with interconnecting pores of 60 microns or greater average diameter. Collagen is deposited within the pores to form a highly stable infection-resistant complex that does not behave as a foreign body, and becomes effectively integrated with the tissues into which it was placed. For a porous compound to be effective as an implant material, it must be biocompatible, mechanically stable, and have stable, interconnecting pores that are large enough to allow tissue ingrowth. The material must be nontoxic and nonimmunogenic, have a stable shelf life, and importantly, it must have good handling characteristics and be sufficiently easy to use in a clinical setting. Present porous implant materials have two significant disadvantages; due to their highly porous structure: the surface of such materials is rough and abrasive, and has a high coefficient of friction when in contact with tissues. This is especially true for porous metal implants with a negative or foam-like structure which may be extremely abrasive, especially if they have large pore sizes. It can therefore be difficult to move porous implants into position during surgery, and the implant surface tends to collect debris such as fat and cellular material which can later become necrotic and harbor infection. There is a need to reduce the surface roughness without compromising the porosity of the material, and to prevent accumulation of debris. This can be achieved by filling or covering the pores with a resorbable or soluble substance.
Therefore, it is another object of this invention to provide a porous implant in which the pores are filled or covered with a resorbable substance that is water soluble and becomes lubricious when wet, resulting in an implant with a smooth surface, without cavities in which debris can become trapped, and with a lubricating layer which helps the surgeon to slide the implant through tissue planes during placement.
In the fields of medicine, surgery, and dentistry, there is a need for an implantable material that contains a particulate component to serve as a framework for tissue ingrowth. The particulate component can be selected from a broad range of natural and synthetic implantable substances, including, but not limited to, native autogenous bone or cartilage, bone or cartilage from other sources that is either grafted directly or after processing, collagen, hydroxyapatite, polymethylmethacrylate (PMMA), polytetrafluoroethylene (PTFE), polyethyllone, and dimethylpolysiloxane. The performance of particulate implants are markedly improved by the addition of a matrix to temporarily adhere the particles to one another, and to form a putty that serves to improve the handling characteristics and to act as a delivery system. The majority of matrices disclosed in the prior art are hydrogels, and they include collagen, glycerol, polysaccharides, mucopolysaccharides, hyaluronic acid, and plasdones (e.g., polyvinylpyrrolidone, PVP). They are not essential for this invention.
Collagen, in the form of gelatin) has been used in ARTEPLAST® from Rofil Medical International. It is an injectable material comprised of microspheres of poly-methylmethacrylate (PMMA) suspended in a gelatin solution. Following implantation, the gelatin is resorbed and replaced by native collagen. Another formulation, ARTE-COLL® is a product currently available in Europe and Canada. It is comprised of smooth PMMA spheres, suspended in bovine collagen from a closed pharmaceutical herd at a concentration of 25% PMMA/75% collagen, by weight with 0.3% lidocaine. Because ARTECOLL® contains bovine collagen, skin testing for allergy to bovine collagen is recommended. Bovine collagen carries the risk of an immunogenic reaction by the recipient patient. Recently, it has been found that a disease of cattle, bovine spongiform encephalopathy (BSE) is transmitted from bovine tissue to humans. Thus, bovine collagen carries a risk of disease transmission and is not a desirable matrix for allograft bone. Human collagen is free of these animal-based diseases. But, collagen absorbs slowly in the human body, particularly in a bony site with a low degree of vascularity.
Glycerol is used as a matrix for demineralized allograft bone in the form of a gel. For example, GRAFTON® from Osteotech is a simple mixture of glycerol and lyophilized, demineralized bone powder (U.S. Pat. No. 5,073,373). GRAFTON® works well to allow the surgeon to place the ailograft bone at the site. But glycerol has a very low molecular weight (92 daltons) and is very soluble in water, the primary component of the blood which flows at the surgical site. Glycerol also experiences a marked reduction in viscosity when its temperature rises from room temperature (typically 22° C. in an operating room) to the patient's body temperature (typically 37° C.). This combination of high water solubility and reduced viscosity causes the allograft bone with a glycerol matrix to be runny and to flow away from the site almost immediately after placement. This prevents the proper retention of the allograft bone within the site as carefully placed by the surgeon. The use of the low-molecular weight glycerol carrier also requires a high concentration of glycerol to be used to achieve the bulk viscosity. Glycerol and other low-molecular weight organic solvents are also toxic and irritating to the surrounding tissues.
U.S. Pat. No. 4,191,747 discloses a bone defect treatment with denatured bone meal freed from fat and ground into powder. The bone meal is mixed with a polysaccharide in a solution of saline and applied to the bone defect site. U.S. Pat. No. 5,290,558 discloses a flowable, demineralized bone powder composition using an osteogenic bone powder mixed with a low molecular weight polyhydroxy compound from 2 carbons to about 18 carbons in chain length including a number of classes of different sugars such as monosaccharides, disaccharides, water-dispersible oligosaccharides, and polysacaharides. U.S. Pat. No. 5,356,629 discloses making a rigid gel in the form of a bone cement to fill defects in bone by mixing biocompatible particles preferably PMMA coated with polyhydroxyethylmethacrylate in a matrix (e.g., hyaluronic acid) to obtain a molded semisolid mass which can be suitably worked for implantation into bone. The hyaluronic acid can also be utilized in monomeric form or in polymeric form preferably having a molecular weight not greater than about one million daltons. It is noted that the nonbioabsorbable but biocompatible particles can be derived from xenograft bone, homologous bone, autogenous bone, as well as other substances. The bioactive substance can also be an osteogenic agent such as demineralized bone powder, in addition to morselized cancellous bone, aspirated bone marrow, and other autogenous bone sources. This is a cement used for implantation of hip prosthesis.
U.S. Pat. No. 6,281,195 discloses a poloxamer hydrogel matrix for the delivery of osteogenic proteins. In particular, poloxamer 407 (PLURONIC™ F127) is used in the form of a hydrogel. Int'l Patent Application PCT/US2004/004174 teaches the use of alloys of alkylene oxide block copolymers and random alkylene oxide copolymers for medical applications, and these formulations also do not rely on water for their utility. But, the alkylene oxide copolymer alloys and the random alkylene oxide copolymers have overall hydrophilic properties, and thus may share some of the limitations of hydrogels with regard to their swelling tendency after implantation.
Therefore, it is yet another object of this invention to provide a nonhydrogel polymer matrix for certain particulate materials used in medicine, dentistry, and surgery which provides a superior combination of adhesive and cohesive properties, ease of handling, optimal retention time at the site of application, minimal swelling, and which is made from nonbiological compounds and is manufactured and used in an essentially anhydrous state.
The present invention teaches that long chain poly(alkylene) molecules suitably modified with poly(ethylene glycol) (PEG) have the properties of greases or waxes but are soluble or dispersible in water; a combination of properties that makes ideally suited for numerous medical, dental and surgical uses. The use of these compounds and novel formulations of these compounds with other materials disclosed herein for such applications have not previously been.